The instant invention relates generally to bioactive avermectin B.sub.2a derivatives which have been modified in the spiroketal region through nucleophilic addition. It is to be understood that the instant invention encompasses both homogeneous B.sub.2a and B.sub.2b derivatives, as well as naturally occurring mixture of these derivatives.
The avermectin series of compounds, which are isolated from a fermentation broth, having the following structure:
wherein R is the 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group of the structure ##STR1## wherein R is the 4'(.alpha.-L-oleandrosyl)-.alpha.-L oleandrose group of the structure: ##STR2## and wherein the broken line indicates a single or a double bond; R.sub.1 is hydroxy and is present only when said broken line indicates a single bond;
R.sub.2 is iso-propyl or sec-butyl; and
R.sub.3 is methoxy or hydroxy.
There are eight different major avermectin natural product compounds and they are given the designations A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b based upon the structure of the individual compounds.
In the foregoing structural formula, the individual avermectin compounds are as set forth below. (The R group is 4'((.alpha.-L-oleandrosyl)-.alpha.-oleandrose):
______________________________________ R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a (22,23-Double Bond) sec-butyl --OCH.sub.3 A1b (22,23-Double Bond) iso-propyl --OCH.sub.3 A2a --OH sec-butyl --OCH.sub.3 A2b --OH iso-propyl --OCH.sub.3 B1a (22,23-Double Bond) sec-butyl --OH B1b (22,23-Double Bond) iso-propyl --OH B2a --OH sec-butyl --OH B2b --OH iso-propyl --OH ______________________________________
The avermectin compounds are generally isolated as mixtures of a and b components. Such compounds differ only in the nature of the R.sub.2 substituent and the minor structural differences have been found to have very little effect on the isolation procedures, chemical reactivity and biological activity of such compounds.
The avermectin class of macrocyclic lactones exhibit unprecedented insecticidal and antiparasitic bioactivities, as disclosed in U.S. Pat. Nos. 4,895,837; 4,550,160; and 4,310,519, the entirety of which are hereby incorporated by reference. Useful modifications of these compounds, however, prove difficult, given avermectins's extreme sensitivity to acidic and basic media employed in traditional chemical techniques.
The instant invention achieves a modification of avermectin to yield a bioactive analog, notwithstanding these synthesis constraints, by a novel substitution at the spiroketal region of the avermectin molecule (C-17-21-25-dioxaspirane substructure) of substituents selected from the group consisting of hydrogen, thioalkyl, thioalkenyl, substituted thioalkyl, thioalkenyl groups, cyano, and heterocyclic nucleophiles derived from a variety of thiols. These avermectin derivatives are prepared by reaction of organometallic reagents with protected avermectin compounds.
Generally, avermectin derivatives of the instant invention are described by the following formulae (III): ##STR3## wherein:
R.sub.1 is hydrogen, hydroxy, oxo, thiophenyl, thiophenyl substituted with halogen, thiopyridyl, thiothiazolyl, thioimidazolyl, thioacetyl, thioalkyl, and their sulfoxide and sulfone oxidation products;
R.sub.2 is hydrogen, hydroxy, thiophenyl, thiophenyl substituted with halogen, cyano, thiopyridyl, thiothiazolyl, thioimidazolyl, thioacetyl, thioalkyl, and their sulfoxide and sulfone oxidation products;
R.sub.3 is methyl;
R.sub.4 is H or alkyl, alkenyl, branched-alkyl, cycloalkyl;
R.sub.5 is H, alkyl, or alkenyl, provided one of R.sub.4 or R.sub.5 is H;
R.sub.6 is OH, oxo, or NOH;
R.sub.7 is H, OH, R.sub.8 -(oleandrosyl).sub.n, (n=1,2,) fluoro, chloro, OCH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3, ##STR4## where R.sub.8 is connected to the 4' or 4" carbon atoms by a single bond and is hydroxy, lower alkanoyloxy, lower alkoxy, amino, N-lower alkylamino, N,N-diloweralkylamino, N-loweralkanoylamino, N-lower alkyl-N-lower alkanoylamino, N-lower-alkyl silyloxy or phenoxyloweralkanoyloxy, or R.sub.8 is attached to the 4' or 4" carbon atoms by a double bond and is oxo, semicarbazano, N-lower-alkylsemicarbazano, N,N-diloweralkanoylamino, loweralkanoyhydrazono or loweralkylbenzoylhydrazono.
Avermectin derivatives of the instant invention include:
24-(4-fluoro-phenylthio)-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-24-(4-fluoro-thiophenyl)-avermectin B2a/2b; PA0 13-epi-0-acetyl-24-(4-fluoro-thiophenyl)-avermectin B2a/2b aglycone; PA0 13-deoxy-24-(4-fluoro-thiophenyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(4-fluoro-thiophenyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(4-fluoro-thiophenyl)-avermectin B2a/2b aglycone-5-oxime; PA0 24-(4-fluoro-thiophenyl)-avermectin B2a/2b-5-oxime; PA0 22,23-dihydro-23-deoxy-23-(4-fluoro-thiophenyl)-24-hydroxy-avermectin B2a/2b. PA0 4"-epi-acetylamino-4"-deoxy-23-deoxy-23-(4-fluorothiophenyl)-24-hydroxy-ave rmectin B2a/2b; PA0 13-epi-0-acetyl-23-deoxy-23-(4-fluoro-thiophenyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-deoxy-23-deoxy-23-(4-fluoro-thiophenyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(4-fluorothiophenyl)-24-hydroxy-avermect in B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(4-fluorothiophenyl)-24-hydroxy-avermect in B2a/2b aglycone-5-oxime; PA0 23-deoxy-23-(4-fluoro-thiophenyl)-24-hydroxy-avermectin B2a/2b-5-oxime; PA0 24-(2-thiopyridyl)-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-24-(2-thiopyridyl)-avermectin B2a/2b; PA0 13-epi-0-acetyl-24-(2-thiopyridyl)-avermectin B2a/2b aglycone; PA0 13-deoxy-24-(2-thiopyridyl)-avermectin B2a/2b aglycone PA0 13-epi-fluoro-13-deoxy-24-(2-thiopyridyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(2-thiopyridyl)-avermectin B2a/2b aglycone-5-oxime; PA0 24-(2-thiopyridyl)-avermectin B2a/2b-5-oxime; PA0 23-deoxy-23-(2-thiopyridyl)-24-hydroxy-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-23-deoxy-23-(2-thiopyridyl)-24-hydroxy-avermect in B2a/2b; PA0 13-epi-0-acetyl-23-deoxy-23-(2-thiopyridyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-deoxy-23-deoxy-23-(2-thiopyridyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(2-thiopyridyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(2-thiopyridyl)-24-hydroxy-avermectin B2a/2b aglycone-5-oxime; PA0 23-deoxy-23-(2-thiopyridyl)-24-hydroxy-avermectin B2a/2b-5-oxime; PA0 24-(4-thiopyridyl)-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-24-(4-thiopyridyl)-avermectin B2a/2b; PA0 13-epi-0-acetyl-24-(4-thiopyridyl)-avermectin B2a/2b aglycone; PA0 13-0-methoxy-ethoxy-methyl-24-(4-thiopyridyl)-avermectin B2a/2b aglycone; PA0 4'-0-methoxy-ethoxy-methyl-24-(4-thiopyridyl)-avermectin B2a/2b monosaccharide; PA0 13-deoxy-24-(4-thiopyridyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(4-thiopyridyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(4-thiopyridyl)-avermectin B2a/2b aglycone-5-oxime; PA0 24-(4-thiopyridyl)-avermectin B2a/2b-5-oxime; PA0 23-deoxy-23-(4-thiopyridyl)-24-hydroxy-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-23-deoxy-23-(4-thiopyridyl)-24-hydroxy-avermect in B2a/2b; PA0 13-epi-0-acetyl-23-deoxy-23-(4-thiopyridyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 4'-0-methoxy-ethoxy-methyl-23-(4-thio-pyridyl)-24-hydroxy-24-methyl-avermec tin B2a/2b monosaccharide; PA0 13-0-methoxy-ethoxy-methyl-23-deoxy-23-(2-thiopyridyl)-24-hydroxy-avermecti n B2a/2b aglycone; PA0 4'-0-methoxy-ethoxy-methyl-22-hydro-23-deoxy-23-(2-thiopyridyl)-24-hydroxy- avermectin B2a/2b monosaccharide; PA0 13-deoxy-23-(4-thiopyridyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(4-thiopyridyl)-24-hydroxy-24-methyl-ave rmectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(4-thio-pyridyl)-24-hydroxy-avermectin B2a/2b aglycone-5-oxime; PA0 23-deoxy-23-(4-thiopyridyl)-24-hydroxy-avermectin B2a/2b-5-oxime; PA0 24-(2-mercaptothiazolyl)-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-24-(2-mercaptothiazolyl)-avermectin B2a/2b; PA0 13-epi-0-acetyl-24-(2-mercaptothiazolyl)-avermectin B2a/2b aglycone; PA0 13-deoxy-24-(2-mercaptothiazolyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(2-mercaptothiazolyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(2-mercaptothiazolyl)-avermectin B2a/2b aglycone-5-oxime; PA0 24-(2-mercaptothiazolyl )-avermectin B2a/2b-5-oxime; PA0 23-deoxy-23-(2-mercaptothiazolyl)-24-hydroxy-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-23-deoxy-23-(2-mercaptothiazolyl)-24-hydroxy-av ermectin B2a/2b; PA0 13-epi-0-acetyl-23-deoxy-23-(2-mercaptothiazolyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-deoxy-23-deoxy-23-(2-mercaptothiazolyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(2-mercaptothiazolyl)-24-hydroxy- 24-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(2-mercaptothiazolyl)-24-hydroxy-avermec tin B2a/2b aglycone-5-oxime; PA0 23-deoxy-23-(2-mercaptothiazolyl)-24-hydroxy-avermectin B2a/2b-5-oxime; PA0 24-(2-mercaptoimidazolyl)-avermectin B2a/2b PA0 4"-epi-acetylamino-4"-deoxy-24-(2-mercaptoimidazolyl)-avermectin B2a/2b; PA0 13-epi-0-acetyl-24-(2-mercaptoimidazolyl)-avermectin B2a/2b aglycone; PA0 13-deoxy-24-(2-mercaptoimidazolyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(2-mercaptoimidazolyl)-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-(2-mercaptoimidazolyl)-avermectin B2a/2b aglycone-5-oxime; PA0 24-(2-mercaptoimidazolyl)-avermectin B2a/2b-5-oxime; PA0 23-deoxy-23-(2-mercaptoimidazolyl)-24-hydroxy-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-23-deoxy-23-(2-mercaptoimidazolyl)-24-hydroxy-a vermectin B2a/2b; PA0 13-epi-0-acetyl-23-deoxy-23-(2-mercaptoimidazolyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-deoxy-23-deoxy-23-(2-mercaptoimidazolyl)-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(2-mercaptoimidazolyl)-24-hydroxy-averme ctin B2a/2b aglycone PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-(2-mercaptoimidazolyl)-24-hydroxy-averme ctin B2a/2b aglycone-5-oxime; PA0 23-deoxy-23-(2-mercaptoimidazolyl)-24-hydroxy-avermectin B2a/2b-5-oxime; PA0 24-thioacetyl-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-24-thioacetyl-avermectin B2a/2b; PA0 13-epi-0-acetyl-24-thioacetyl-avermectin B2a/2b aglycone; PA0 13-deoxy-24-thioacetyl-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-thioacetyl-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-thioacetyl-avermectin B2a/2b aglycone-5-oxime; PA0 24-thioacetyl-avermectin B2a/2b-5-oxime; PA0 23-deoxy-23-thioacetyl-24-hydroxy-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-23-deoxy-23-thioacetyl-24-hydroxy-avermectin B2a/2b; PA0 13-epi-0-acetyl-23-deoxy-23-thioacetyl-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-deoxy-23-deoxy-23-thioacetyl-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-thioacetyl-24-hydroxy-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-23-deoxy-23-thioacetyl-24-hydroxy-avermectin B2a/2b aglycone-5-oxime; PA0 23-deoxy-23-thioacetyl-24-hydroxy-avermectin B2a/2b-5-oxime; PA0 24-cyano-avermectin B2a/2b; PA0 4"-epi-acetylamino-4"-deoxy-24-cyano-avermectin B2a/2b; PA0 13-epi-0-acetyl-24-cyano-avermectin B2a/2b aglycone; PA0 13-deoxy-24-cyano-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-cyano-avermectin B2a/2b aglycone; PA0 13-epi-fluoro-13-deoxy-24-cyano-avermectin B2a/2b aglycone-5-oxime; and PA0 24-cyano-avermectin B2a/2b-5-oxime.